Identification of means to prevent stress-related psychiatric disorders such as depression & anxiety is of primary importance. One manipulation with established stress resilient effects is exercise. We have observed that rats allowed access to running wheels are protected against the depression- & anxiety-like consequences of uncontrollable stress, or learned helplessness (LH). Growing evidence indicates that LH behaviors are produced by hyperactivation & sensitization of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN). Hyperactivation of DRN 5-HT neurons during stress could lead to later sensitization of these neurons by desensitizing 5-HT1A inhibitory autoreceptors in the DRN. Results from our prior work & preliminary studies suggest that wheel running prevents LH by constraining the activity of DRN 5-HT neurons during stressor exposure & preventing the desensitization of 5-HT1A autoreceptors. Constraint over 5-HT neural activity could be an adaptive feature of the stress response that is dysregulated in stress-related psychiatric disorders but facilitated by prior voluntary exercise. Understanding how the experience of exercise is communicated to the DRN to result in stress resilience is a primary goal of this project that has clear clinical implications for the prevention of stress-related disorders. Exercise is a unique behavioral manipulation that will likely recruit neurocircuits that together result in unique adaptations in the brain. To facilitate identification of these neurocircuits, we propose an innovative approach of controllable / yoked uncontrollable wheel running. Although voluntary wheel running is associated with stress resilience, forced exercise often fails to produce stress protective effects despite considerable fitness benefits. These data suggest that activity or fitness per se is not sufficient to produce stress resilience. Instead, exercise plus the psychological variable of perceived control may be critical. This is an important distinction because it implies involvement of distinct neural substrates involved in the perception of control (such as the medial prefrontal cortex; mPFC), vs. those simply recruited by physical activity per se (such as the noradrenergic system), in the stress resilience produced by exercise. Indeed, we have observed that voluntary exercise recruits both of these systems; repeated activation of which could contribute to the increase in DRN 5- HT1A autoreceptors by inhibiting the activity of the 5-HT1A gene repressor Freud-1. The current project tests the hypotheses that 1) wheel running prevents LH by preventing DRN 5-HT1A autoreceptor desensitization &/or increasing mPFC-inhibition of the DRN during stress, 2) the effects of wheel running on behavior & 5-HT1A autoreceptors are dependent on exercise controllability, & 3) repeated activation of the mPFC &/or DRN 11- ADRs contribute to the increase in 5-HT1A autoreceptors & the protective effect of wheel running against LH. PUBLIC HEALTH RELEVANCE: The goal of the current proposal is to identify how the experience of exercise is communicated to the central serotonergic system to result in resilience against stress- induced anxiety, focusing specifically on central circuits converging on the 5-HT1A autoreceptor. The results of this work will improve our basic understanding of the effects of stressor exposure and exercise on serotonin systems, and could lead to novel approaches for the prevention or treatment of stress-related psychiatric disorders.